Project Summary The molecular mechanisms that cause spontaneous neurodegeneration remain poorly understood. Here, we propose a novel hypothesis for the molecular events that lead to the generation of misfolded proteins and their accumulation in neurotoxic protein aggregates. Prompted by our recent discoveries on the mechanisms of olfactory receptor (OR) gene regulation, we propose that olfactory neurons could be used as early molecular sensors for neurodegenerative disorders. This hypothesis is supported by two key observations. First, Lsd1, the histone demethylase that activates OR transcription, releases hydrogen peroxide in nuclei of olfactory neurons, causing increased DNA oxidation locally, at OR loci, and genome-wide. 8-oxoguanine, the modified base generated by Lsd1-mediated oxidation, is not efficiently repaired in olfactory neurons and can cause frequent G to A conversion during transcription. Consequently, olfactory neurons may have high incidence of missense mutations in their mRNAs, some of which are likely to generate mutant proteins that are prone to misfolding and aggregation. Second, olfactory neurons cannot clear misfolded and aggregated proteins from their endoplasmic reticulum (ER) because they co-opted the unfolded protein response (UPR) pathway towards OR regulation instead of ER homeostasis. This unique combination of regulatory ?side-effects?, i.e. increased mutagenesis rates through DNA oxidation and impaired ability to remove misfolded proteins from the ER, may provide an ideal cellular environment for the generation of misfolded proteins and the accumulation of protein aggregates. Thus, we propose experiments that will further explore this hypothesis and will provide molecular insight to spontaneous neurodegeneration. With the development of novel, whole genome sequencing approaches with base-pair resolution, we will map the location of Lsd1-dependent 8-oxoguanine accumulation and we will quantitate its mutagenic potential during transcription. High throughput in vitro screens combined with mouse genetics will evaluate the contribution of frequent missense mutation in the misfolding and aggregation of proteins previously linked to neurodegeneration. Genetic approaches will determine how the alternative UPR pathway that evolved for OR regulation contributes to the onset of neurodegeneration. Our experiments have paradigm-shifting potential towards the understanding of spontaneous neurodegeneration and may lead to the development of novel molecular tools for its timely diagnosis or reliable prognosis, which could provide decisive advantage towards the prevention and treatment of Alzheimer?s disease.